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The objective of the present investigation was to fabricate composite colloidal particles consisting of a sacrificial, decomposable template of biodegradable nature covered with biocompatible polyelectrolyte multilayers using the layer-by-layer sequential adsorption technique. Poly-dl-lactic acid and poly(dl-lactic-co-glycolic acid) were chosen to design the microparticulate template, and a preliminary feasibility study was carried out with poly(styrene sulfonate sodium)-poly(allylamine hydrochloride) as shell components. The properties of both core-shell and hollow structures obtained by core dissolution were characterized by confocal laser scanning microscopy, microelectrophoresis, scanning force microscopy, and scanning electron microscopy. The concept was then extended to biocompatible polyelectrolytes as shell wall building blocks to deduce stable hollow capsules with tailored properties. Uniform, complete coating with oppositely charged polyelectrolyte pairs was achieved for all the combinations investigated. The results demonstrate that polyester microparticles could serve as viable alternative components to conventionally employed templates to derive hollow capsules with defined size, shape, and shell thickness. With all the components used for fabrication being biocompatible, these polyelectrolyte capsules may find interesting applications in the fields of biology, biochemistry, biotechnology, and drug delivery.

Purpose.-This study was carried out to determine the biodistribution profiles and tumor localization potential of poly(ethylene oxide) (PEO)-modified poly (β-amino ester) (PbAE) as a novel, pH-sensitive biodegradable polymeric nanoparticulate system for tumor-targeted drug delivery.Methods.-The biodistribution studies of PEO-modified PbAE and PEO-modified poly(ɛ-caplactone) (PCL), a non-pH sensitive polymer, nanoparticle systems were carried out in normal mice using 111 indiumoxine [ 111 In] as a lipophilic radiolabel encapsulated within the polymeric matrix and the distribution of the nanoparticles was studied in plasma and all the vital organs following intravenous administration. Solid tumors were developed on nude mice using human ovarian carcinoma xenograft (SKOV-3) and the change in concentrations of tritium [ 3 H]-labeled paclitaxel encapsulated in polymeric nanoparticles was examined in blood, tumor mass and liver.Results.-Study in normal mice with a gamma-emitting isotope [ 111 In] provided a thorough biodistribution analysis of the PEO-modified nanoparticulate carrier systems, while the 3 H-paclitaxel was useful to understand the change in concentration and tumor localization of anticancer compound directly in major sites of distribution. Both PEO-PbAE and PEO-PCL nanoparticles showed long systemic circulating properties by virtue of surface modification with PEO-containing triblock block copolymer (Pluronic ® ) stabilizer. While the PCL nanoparticles showed higher uptake by the reticuloendothelial system (RES), the PbAE nanoparticles effectively delivered the encapsulated payload into the tumor mass.Conclusions.-PEO-modified PbAE nanoparticles showed considerable passive tumor targeting potential in early stages of biodistribution via the enhanced permeation and retention (EPR) mechanism. This prompts a detailed biodistribution profiling of the nanocarrier for prolonged periods of time to provide conclusive evidence for superiority of the delivery system.

A representative poly(β-amino ester) (PbAE) with biodegradable and pH-sensitive properties was used to formulate nanoparticle-based dosage form for tumor-targeted paclitaxel delivery. The polymer undergoes rapid dissolution when the pH of the medium is less than 6.5, and hence is expected to release its contents at once within the acidic tumor microenvironment and endo/lysosome compartments of cells. PbAE nanoparticles were prepared by solvent displacement method and characterized for particle size, charge, and surface morphology. Pluronic ® F-108, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) was blended with PbAE to induce surface modification of the nanoparticles. In vitro cellular uptake of tritiated [ 3 H] paclitaxel in solution form and as nanoparticulate formulation was studied in MDA-MB-231 human breast adenocarcinoma cells grown in 12-well plates. We also examined the intracellular degradation pattern of the formulations within the cells by estimating the drug release profile. Cytotoxicity assay was performed on the formulations at different doses and time intervals. Nanoparticles prepared from poly(ε-caprolactone) (PCL) that do not display pH-sensitive release behavior were used as control. Spherical nanoparticles having positive zeta potential (~ 40 mV) were obtained in the size range of 150-200 nm with PbAE. The PEO chains of the Pluronic ® were well-anchored within the nanomatrix as determined by electron spectroscopy for chemical analysis (ESCA). The intracellular accumulation of paclitaxel within tumor cells was significantly higher when administered in the nanoparticle formulations as compared to aqueous solution. Qualitative fluorescent microscopy confirmed the rapid release of the payload in case of PbAE nanoparticles into the cytosol, while the PCL nanoparticles integrity remained intact. The cytotoxicity assay results showed significantly higher tumoricidal activity of paclitaxel when administered in the nanoparticle formulations. The cell-kill effect was maximal for paclitaxel-loaded PbAE nanoparticles when normalized with respect to intracellular drug concentrations. Thus, PEO-modified PbAE nanoparticles show tremendous potential as novel carriers of cytotoxic agents for achieving improved drug disposition and enhanced efficacy.

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For the development of surface-functionalized gold nanoparticles as cellular probes and delivery agents, we have synthesized hetero-bifunctional poly(ethylene glycol) (PEG, MW 1500) having a thiol group on one terminus and a reactive functional group on the other for use as a flexible spacer. Coumarin, a model fluorescent dye, was conjugated to one end of the PEG spacer and gold nanoparticles were modified with coumarin-PEG-thiol. Surface attachment of coumarin through the PEG spacer decreased the fluorescence quenching effect of gold nanoparticles. The results of cellular cytotoxicity and fluorescence confocal analyses showed that the PEG spacer-modified nanoparticles were essentially non-toxic and could be efficiently internalized in the cells within 1 hour of incubation. Intracellular particle tracking using a Keck 3-D Fusion Microscope System showed that the functionalized gold nanoparticles were rapidly internalized in the cells and localized in the peri-nuclear region. Using the PEG spacer, the gold nano-platform can be conjugated with a variety of biologically relevant ligands such as fluorescent dyes, antibodies, etc in order to target, probe, and induce a stimulus at the target site.

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PEO-modified PbAE nanoparticles are a unique pH-sensitive drug delivery system that elicits enhanced efficacy and safety profile in solid tumor therapy.